1. Field of the Invention
This invention relates to a novel method for a treatment of ophthalmic diseases associated with increased intraocular pressure. Certain known compounds have been found to lower intraocular pressure in mammals and would, therefore, be useful in the treatment of glaucoma or other ophthalmic diseases which are accompanied with or caused by increased intraocular pressure.
2. Related Disclosures
Intraocular pressure is as constant for the organism as is temperature, pulse, and blood pressure. Like many other autonomic body functions, it has a circadian rhythm over 24 hours with a sinusoidal up and down pattern. A constant intraocular pressure within the limits of circadian fluctuation (15-20 mm Hg) is a prerequisite for normal visual function and it is tied to the normal relationship between cornea, lens, and retina as well as to the clarity of media. In the interest of vision, under the normal circumstances, every elevation of intraocular pressure is immediately offset in the opposite direction by regulatory mechanisms. Certain local and central nervous functions insure that the equilibrium is immediately re-established. Ophthalmology, Fritz Hollwich, George Thieme Publishers, 127, (1979).
Many ophthalmic diseases are ocular disorders which are either caused by or associated with increased intraocular pressure. Such complications very often lead to an impairment of the eyesight or blindness. Among those diseases considered most dangerous which are associated with increased intraocular pressure belongs a group of ocular diseases called glaucoma.
Glaucoma is a group of ocular diseases with common features of abnormally elevated intraocular pressure which slowly causes progressive loss of peripheral visual fields. When untreated, glaucoma causes a loss of central vision and ultimate blindness. A number of diverse clinical cases are included in the category of glaucoma. The causes of the development of glaucoma are mostly unknown. Glaucoma is usually treated topically by agents which constrict the pupil of the eye, such as pilocarpine or carbachol, systemically by osmotic agents or carbonic anhydrase inhibitors, or by surgery. The Merck Manual, 13th Ed., 1702, (1977).
To define glaucoma in its simplest form, one can state that there is an intraocular pressure elevation which rests upon an imbalance between aqueous inflow and outflow. The etiology of this imbalance is highly variable.
The glaucoma is generally categorized as primary, secondary, congenital and absolute, and these categories are described in detail in The Merck Manual cited above.
Primary glaucoma is generally sub-classified into two categories, chronic simple (open-angle) glaucoma and acute or chronic congestive (angle-closure) glaucoma.
Chronic simple open-angle glaucoma is the most prevalent form of glaucoma, and the one which will be most responsive to a treatment of topical administration of the compounds of this invention. It is a disorder characterized by a gradual rise in intraocular pressure, causing slowly progressive loss of peripheral vision and, when uncontrolled, late loss of central vision and ultimate blindness. The reason for increased ocular pressure in open angle glaucoma is that outflow of aqueous trabecular meshwork into Schlemm's canal is retarded and the resistance to aqueous outflow is elevated. Hence, the intraocular pressure is also elevated.
A congestive angle-closure glaucoma is subdivided into acute angle-closure and chronic angle-closure glaucoma.
Acute angle-closure glaucoma is a disorder characterized by attacks of suddenly increased intraocular pressure to three to five times normal values which occurs over a period of a few hours. The reason for increased intraocular pressure is an acute blockage of aqueous outflow. Each acute attack progressively diminishes vision and contracts the visual field.
Chronic angle-closure glaucoma is a disorder characterized by recurrent attacks, usually unilateral, of increased intraocular pressure, pain, and impaired vision--similar to those of acute angle-closure glaucoma, but less severe.
Secondary glaucoma is usually a product of numerous underlying diseases such as intraocular inflammation, perforating injuries with lesions to the ciliary body, a development of anterior synechiae, swelling or luxation of the lens, vascular diseases and others.
Absolute glaucoma is the last stage of any form of uncontrolled glaucoma. The eye is blind from progressive atrophy of the optic nerve head.
Presently predominant medical treatment of all types of primary glaucoma (simple open-angle, acute angle-closure and chronic glaucoma) is a topical administration of pilocarpine timolol maleate, or cholinesterase inhibitors including eserine. The goal of this therapy is to lower the intraocular pressure. Other systemic medications such as acetazolamide, an enzyme inhibitor which acts specifically on carbonic anhydrases, are available for treatment of glaucoma. In the eye, inhibitory action of acetazolamide decreases the secretion of aqueous humor and results in a drop in intraocular pressure, a reaction considered desirable in cases of glaucoma. Other forms of glaucoma may be treated similarly, i.e. by topical administration of pilocarpine, eserine, timolol maleate, corticosteroids or anti-inflammatory agents, or systemically by carbonic anhydrase inhibitors. All forms of glaucoma may be treated surgically. PDR, 36th Ed., 1046, (1982).
The goal of topical and systemic therapy of glaucoma is to decrease the intraocular pressure. Existing therapy, especially topical therapy with pilocarpine, eserine or timolol, however, require the strong, high percentage topical drops applied in rather short time periods. Moreover, many of the topically used drugs also have undesirable systemic secondary effects.
Attempts to find effective treatment of ocular hypertension are known. Catecholamine treatment of ocular hypertension is described in U.S. Pat. No. 4,275,074. Treating glaucoma and lowering intraocular pressure by topical administration of R,R-labetalol is described in U.S. Pat. No. 4,312,863. N-Demethylated carbachol reducing intraocular pressure in glaucomatous dogs is described in Invest. Ophthalmic Vis. Sci., 19:1198 (1980). U.S. Pat. No. 4,322,425 describes an ophthalmic composition containing a carbostyril derivative useful for treatment of glaucoma.
Applicants have found that certain known thiazoles, particularly acylaminothiazoles and thiazolecarboxamides, are useful for decreasing intraocular pressure when applied topically to the eye and hence, useful for treatment, prevention or inhibition of primary or secondary glaucoma or any other ophthalmic disease which is associated with or caused by ocular hypertension. These compounds show high potency to decrease intraocular pressure comparable to timolol maleate, which is a commonly used topical intraocular hypotensive. Beside the fact that these compounds are extremely potent when administered topically, they do not cause secondary symptoms usually accompanying the systemic treatment of hypertension in the eye and thus their use is advantageous against other known ocular hypotensive drugs. For example, timolol maleate when applied topically may be absorbed systemically and can cause bronchospastic disease, sinus bradycardia, cardiogenic shock, cardiac failure, etc. PDR, 36th Ed., pp. 1284 (1982). On the contrary, compounds of this invention show no systemic activity whatsoever and when applied topically they seem not to be absorbed systemically.
Compounds which are the subject of this invention and those having similar structures to these compounds are known and have been described in U.S. Pat. No. 3,897,441; U.S. Pat. No. 4,064,258; and U.S. Pat. No. 3,850,945. The compounds described in these patents exhibit cardiovascular activities and are useful in the treatment of abnormal heart conditions as well as systemic hypertension in mammals. These compounds were not previously administered topically, i.e., directly to the eye, to prevent, inhibit or treat ophthalmic diseases probably because their non-irritating properties to the eye were unknown, and are unexpected and surprising.